Composition containing polycationic triblock copolymer, polyanionic polymer and physiologically active peptide

Abstract

[Problem] To provide a physiologically active peptide-loaded stable composition for injection into living bodies. [Solution] A composition containing a triblock copolymer represented by formula (I), a polyanionic polymer and a physiologically active peptide: CNR-PEG-CNR  (I) in the formula, CNR moieties are each independently a polymer segment containing a repeating unit that contains, as a part of a pendant group, a cyclic nitroxide radical bonded to a main polymer chain via a linking group that contains at least one amino group, and PEG is a segment that contains poly(ethylene glycol).

The invention claimed is: 
     
       1. A composition comprising a triblock copolymer represented by formula (II), a polyanionic polymer and a physiologically active peptide: 
       
         
           
           
               
               
           
         
         in the formula, 
         L 1  groups are linking groups that may be the same as, or different from, each other, 
         L 2  groups are each independently a —C 1-6  alkylene-NH—(C 1-6  alkylene)q- group, with q being an integer of 0 or 1, 
         wherein in at least one of the L 2  groups q=1, 
         R groups are each independently such that at least 50% of the total number (n) of R groups are residues of cyclic nitroxide radical compounds selected from the group consisting of 2,2,6,6-tetramethylpiperidin-1-oxyl-4-yl groups, 2,2,5,5-tetramethylpyrrolidin-1-oxyl-3-yl groups, 2,2,5,5-tetramethylpyrrolin-1-oxyl-3-yl groups, 2,4,4-trimethyl-1,3-oxazolidin-3-oxyl-2-yl groups, 2,4,4-trimethyl-1,3-thiazolidin-3-oxyl-2-yl groups and 2,4,4-trimethyl-imidazolidin-3-oxyl-2-yl groups, with the remaining R groups, when present, being hydrogen atoms, halogen atoms or hydroxyl groups, 
         terminal H groups may, in some cases, each independently be substituted by groups selected from among arylthiocarbonylthio groups, alkylthiocarbonylthio groups, alkoxythiocarbonylthio groups and sulfanyl groups, 
         m is an integer between 20 and 5,000, and 
         each instance of n is independently an integer between 3 and 1,000. 
       
     
     
       2. The composition according to  claim 1 , wherein the L 1  groups are each independently selected from the group consisting of single bonds, —S—(CH2) c - groups, —S—(CH2) c CO— groups, —(CH2) c S— groups, —CO(CH2) c S— groups, m- or p-phenylene groups, m- or p-xylylene groups and alkylene groups, c is an integer between 1 and 5, with these linking groups able to be in the opposite direction from that shown in formula (II) in cases where the linking groups are not directionally equivalent,
 R is selected from among groups represented by the following formulae: 
 
       
         
           
           
               
               
           
         
         in the formulae, R′ is a methyl group, and 
       
       at least 80% of the total number (n) of R groups are groups represented by the formula shown above. 
     
     
       3. The composition according to  claim 1 , wherein the polyanionic polymer is one or more types selected from the group consisting of poly(acrylic acid), poly(methacrylic acid), poly(sulfonic acid), polyanionic polysaccharides and anionic proteins. 
     
     
       4. The composition according to  claim 1 , wherein the physiologically active peptide is selected from the group consisting of enzyme proteins, antigenic proteins, antibodies, cytokines, peptide hormones and antimicrobial peptides. 
     
     
       5. The composition according to  claim 1 , wherein the ratio of a total anionic charge relative to a total cationic charge from the triblock copolymer, the polyanionic polymer and the physiologically active peptide is between 10:1 and 1:10 in an aqueous solution. 
     
     
       6. The composition according to  claim 1 , which is present as polyion complex micelles having an average particle diameter, as measured by a dynamic light scattering (DLS) method, of 10 to 300 nm in an aqueous solution. 
     
     
       7. The composition according to  claim 1 , which forms a gel according to changes in the ionic strength in the aqueous solution and/or changes in temperature. 
     
     
       8. A gel-forming medical composition comprising a polyion complex formed from the composition according to  claim 1 , and a pharmaceutically acceptable diluent or excipient. 
     
     
       9. A triblock copolymer represented by formula (II) 
       
         
           
           
               
               
           
         
         in the formula, 
         L 1  groups are linking groups that may be the same as, or different from, each other, 
         L 2  groups are each independently a —C 1-6  alkylene-NH—(C 1-6  alkylene)q- group, with q being an integer of 0 or 1, 
         wherein in at least one of the L 2  groups q=1, 
         R groups are each independently such that at least 50% of the total number (n) of R groups are residues of cyclic nitroxide radical compounds selected from the group consisting of 2,2,6,6-tetramethylpiperidin-1-oxyl-4-yl groups, 2,2,5,5-tetramethylpyrrolidin-1-oxyl-3-yl groups, 2,2,5,5-tetramethylpyrrolin-1-oxyl-3-yl groups, 2,4,4-trimethyl-1,3-oxazolidin-3-oxyl-2-yl groups, 2,4,4-trimethyl-1,3-thiazolidin-3-oxyl-2-yl groups and 2,4,4-trimethyl-imidazolidin-3-oxyl-2-yl groups, with the remaining R groups, when present, being hydrogen atoms, halogen atoms or hydroxyl groups, 
         terminal H groups are each substituted by groups selected from among arylthiocarbonylthio groups, alkylthiocarbonylthio groups, alkoxythiocarbonylthio groups and sulfanyl groups, 
         m is an integer between 20 and 5,000, and 
         each instance of n is independently an integer between 3 and 1,000. 
       
     
     
       10. The triblock copolymer according to  claim 9 , wherein the L 1  groups are each m- or p-phenylene groups, m- or p-xylylene groups or alkylene groups. 
     
     
       11. The composition according to  claim 9 , wherein the polyanionic polymer is one or more types selected from the group consisting of poly(acrylic acid), poly(methacrylic acid), poly(sulfonic acid), polyanionic polysaccharides and anionic proteins. 
     
     
       12. The composition according to  claim 9 , wherein the ratio of a total anionic charge relative to a total cationic charge from the triblock copolymer, the polyanionic polymer and the physiologically active peptide is between 10:1 and 1:10 in an aqueous solution. 
     
     
       13. A gel-forming medical composition comprising a polyion complex formed from the composition according to  claim 9 , and a pharmaceutically acceptable diluent or excipient.